Tears play an important role in maintaining the normal visual function. Tears cover the surface of cornea and conjunctiva to retain the wettability thereof and, at the same time, tears fill a depression due to a microvillus on the corneal surface to make the surface smooth, therefore, it becomes possible to obtain a clear image. In addition, epithelial cells of cornea and conjunctiva actively metabolize cellular components and unnecessary cells and metabolites are detached and discharged from the most superficial surface, tears not only wash out them but also supplement necessary oxygen and nutrients. Further, tears wash out foreign matters which intrude on the surface of cornea and conjunctiva, and play a role of defending infection against viruses, bacteria and fungi which have invaded from the outside by the bacteriostatic action of tears. Furthermore, tears work as a synovia between an eyelid and cornea and conjunctiva so that nictitating and eyeball movement are smoothly done. Thus, tears are a minor amount of fluid for forming a slight thin film on the surface of cornea and conjunctiva, and are indispensable for maintaining the transparency and the homeostatis of cornea by various elaborate mechanisms.
The state where a secretion disorder of tears causes abnormality on the surface of cornea and conjunctiva is generally called dry eye. When a disorder of cornea and conjunctiva due to dry eye is caused, supplement of artificial tears, dropping of a viscoelastic substance having high moisture retention such as hyaluronic acid into eyes, and use of dry eye spectacles for keeping the eye surface wet and ameliorating dry symptom are performed. However, while symptom can be ameliorated by these symptomatic treatment methods, these treatment methods are not an etiotropic method for fundamental treatment. Since it is thought that tears have the effect of curing corneal and conjunctival disorder due to dry eye by their natural function as described above, a compound which directly acts on lacrimal gland and promotes tear secretion is expected to be a useful remedy for dry eye and diseases associated with dry eye.
Lacrimal glands are controlled by parasympathetic nerve and sympathetic nerve and the former is dominant. Parasympathetic nerve secretes acetylcholine and VIP (Vasoactive Intestinal Peptide). On the other hand, sympathetic nerve secretes norepinephrine and neuropeptide Y. Acetylcholine, norepinephrine and VIP mainly stimulate lacrimal glands (Dartt D A et al., Adv Eep Med Biol 438: 113-121, 1998). Acetylcholine is shown to activate muscarinic cholinergic route and be involved also in lacrimal secretion (Nakamura M et al., Curr Eye Res 16: 614-619, 1997). Norepinephrine is a sympathomimetic amine which binds to adrenaline α and β receptors, and secretes tear protein via an α1 adrenaline receptor (Dartt D A, Curr Eye Res 8:619-636, 1989). VIP is a peptide having various biological activities which relaxes a smooth muscle of a digestive tract and a blood vessel, and it is reported that receptors for this VIP are present in lacrimal glands (Hodges R R et al., Invest Opthalmol Vis Sci 38:610-619, 1997), and actually promotes secretion of protein from lacrimal glands (Dartt D A et al., Am J Physiol 247:G502-509, 1984).
As described above, distribution of receptors such as muscarine, norepinephrine or VIP in lacrimal glands, and further, participation in lacrimal secretion have been shown. However, currently, these physiologically active ingredients have not been put into practice yet as an agent for preventing or treating dry eye based on the lacrimal secretion promoting activity. With respect to VIP, U.S. Pat. No. 4,745,100 discloses a method of promoting lacrimal secretion by topical administration, but there is no specific description of VIP derivatives therein. In addition, peptides exhibiting excellent bronchodilator activities and the digestive tract movement inhibiting activities as VIP derivatives are disclosed in JP-A 8-333276 and JP-A 2001-151799, respectively, but there are no description regarding lacrimal secretion and dry eye in these publications.